molecules Review Venoms of Iranian Scorpions (Arachnida, Scorpiones) and Their Potential for Drug Discovery Seyed Mahdi Kazemi 1,* and Jean-Marc Sabatier 2 1 Zagros Herpetological Institute, No 12, Somayyeh 14 Avenue, 3715688415 Qom, Iran 2 Institute of NeuroPhysiopathology, UMR 7051, Faculté de Médecine Secteur Nord, 51, Boulevard Pierre Dramard-CS80011, 13344-Marseille Cedex 15, France * Correspondence: [email protected] Academic Editor: Ericsson Coy-Barrera Received: 16 March 2019; Accepted: 20 July 2019; Published: 23 July 2019 Abstract: Scorpions, a characteristic group of arthropods, are among the earliest diverging arachnids, dating back almost 440 million years. One of the many interesting aspects of scorpions is that they have venom arsenals for capturing prey and defending against predators, which may play a critical role in their evolutionary success. Unfortunately, however, scorpion envenomation represents a serious health problem in several countries, including Iran. Iran is acknowledged as an area with a high richness of scorpion species and families. The diversity of the scorpion fauna in Iran is the subject of this review, in which we report a total of 78 species and subspecies in 19 genera and four families. We also list some of the toxins or genes studied from five species, including Androctonus crassicauda, Hottentotta zagrosensis, Mesobuthus phillipsi, Odontobuthus doriae, and Hemiscorpius lepturus, in the Buthidae and Hemiscorpiidae families. Lastly, we review the diverse functions of typical toxins from the Iranian scorpion species, including their medical applications. Keywords: scorpion; fauna; venom; toxin; Iran 1. Introduction Scorpions, a characteristic group of arthropods, diverged from other arachnids relatively early, at about 440 million years ago [1,2]. Their morphology has stayed constant since they adapted to a terrestrial habitat. Their morphological stasis has not been, however, an impediment to successfully colonizing different ecological ecosystems such as caves, high peaks, and deserts [3,4]. Morphological phylogenetic analyses suggest that scorpions are sister taxa to either the rest of the arachnids or to the Opiliones [5]. However, recent phylogenomic analysis suggests that scorpions are closely related to spiders and allies, forming the clade Arachnopulmonata [6,7]. Among the 18 scorpion families with more than 2200 species described in the world, about thirty species have been identified as potentially deadly toxic to humans [8,9]. Our studies on scorpions are based on two remarkable aspects of this group: Their evolutionary origin and systematic classification, and the diversity and origin of their venom components, with emphasis on the use of these components as potential sources of molecules with therapeutic applications [10]. Scorpions have fascinated scientists and laypersons for their venom, which is a complex mixture of bioactive components secreted in specialized organs [11]. These animals inject venom to subdue prey or to defend against attackers. Their venoms consist of a variety of toxins, which may vary according to species, habitat, or fluctuations in climate [12]. Within scorpion venom components, the peptidic fraction has been considered a great source of lead compounds for drugs to treat various cancers and infectious diseases [13]. Hence, studies on scorpion venom components are important, especially in terms of medical treatments for human diseases. Molecules 2019, 24, 2670; doi:10.3390/molecules24142670 www.mdpi.com/journal/molecules Molecules 2019, 24, 2670 2 of 20 Here, we review the diversity of scorpions in Iran. We also highlight the importance of the venomic studies of Iranian scorpions. Establishing what is known about of scorpions and scorpion venom in Iran will allow the identification of important gaps to be addressed in the future. 2. Scorpion Species from Iran Iran is a vast land with diverse climates. There are two main mountain ranges in Iran: (1) Alborz; and (2) Zagros and neighboring mountains. Diverse climates in Iran are the direct result of the presence of the Persian Gulf, the Oman Sea bordering Southeastern Iran, and the Caspian Sea in Northern Iran. According to Safaei-Mahroo et al. [14] 16 terrestrial ecoregions have been reported from Iran including: Arabian Desert and East Saharo-Arabian xeric shrublands (0.1%), Azerbaijan shrub desert and steppe (0.4%), Badkhiz-Karabil semi-desert (0.1%), Caspian lowland desert (0.3%), Central Persian desert basins (34.7%), Kopet Dagh semi-desert (0.4 %), Registan-North Pakistan sandy desert (3%), South Iran Nubo-Sindian desert and semi-desert (17.3%), Mesopotamian shrub desert (0.1%), Tigris-Euphrates alluvial salt marsh (0.4%), Kopet Dagh woodlands and forest steppe (1.6%), Kuh Rud and Eastern Iran Montane woodlands (7.5%), Caspian Hyrcanian mixed forests (3.4%), Zagros Mountains forest steppe (21.8%), Alborz Range forest steppe (4.3%), and Eastern Anatolian montane steppe (4.6%). Iran is located in a strategic position in the Palearctic region and is a bridge between the Oriental and African zoogeographical regions, suggesting the possibility of endemic arthropod species in this region. Among these arthropods, scorpions stand out as there are diverse species in desert and semi-desert regions of Iran (for more details see appendix: Table S1). Historically, the fauna of Iran has been studied by many researchers. The earliest descriptions of the first species were made by Olivier (Androctonus crassicauda (Olivier, 1807)) [15]. Later, Alexei Andreevich Byalynitskii-Birulya [16–19] published a series of scorpion studies from Iran that included well known species and several rare taxa [20–26]. In addition, pioneering zoologists such as Pocock [27] and Werner [28] described a few more species in the region. In the middle of the 20th century, Max Vachon carried out preliminary studies on the scorpions of Iran, with a later report of two families, nine genera, and 15 species [29]. Later, Habibi [30] reported 24 species belonging to 11 genera and two families. Farzanpay [31,32] reported fewer species (23 species), but increased the number of genera (17), as well as two families. More recently, Kovaˇrík [23] reported a list of three families, 17 genera, and 32 species of scorpions. A more extensive study of Iranian scorpions continued with publications by Navidpour et al. [33–37], who recorded the dispersal of scorpions in all of Iran. Lastly, Mirshamsi et al. [38] reported 51 species belonging to 18 genera in four families. According to Vachon [29] and Mirshamsi et al. [38], there are Androctonus baluchicus, Androctonus crassicauda, and Androctonus finitimus in Iran. However, Ya˘gmuret al. [39] believed that Androctonus crassicauda and Androctonus robustus are present in Iran while rejecting the occurrence of Androctonus baluchicus and Androctonus finitimus in Iran. Compsobuthus kafkai and Compsobuthus sobotniki were synonymized with Sassanidotus gracilis [37,40]. Farzanpay [32] believed that Hottentotta alticola alticola are present in Iran but Mirshamsi et al. [38] believed that records show Hottentotta alticola alticola are in doubt. Mirshamsi [41] believed that Mesobuthus phillipsi includes the Mesobuthus phillipsi pachysoma and Mesobuthus phillipsi mesopotamicus subspecies. Although Vachon [29], Farzanpay [32], Mirshamsi et al. [38], and Nejati et al. [42], reported Odontobuthus odonturus in Iran, Lowe [43] rejected Odontobuthus odonturus in Iran. Based on field work, study collections, literature reviews, and personal communications, the total number of species confirmed within the Iranian border is 78 species and subspecies belonging to 19 genera and four families. The family Buthidae is the most diverse with 68 species and subspecies (87.17%), followed by Hemiscorpiidae with seven species (8.97%), Scorpionidae with two subspecies (2.56%), and Diplocentridae with one species (1.28%) [23–26,29,32–42,44–49] (Table S2). Forty-five out of 78 species and subspecies of the Iranian scorpions are endemic to Iran (57.69%, for more details see appendix: Tables S1 and S2). Molecules 2019, 24, 2670 3 of 20 3. Previous Studies on Drug Discovery of Scorpion Venoms Animal venoms are a mixture of different compounds for defense and prey capture. Many peptide toxins from deadly animal venoms have been influenced by ion channel (including sodium, potassium, and calcium channels) functions. The ion channels play important roles in the regulation of the heart beat and neuronal excitability [50,51]. Scorpion venoms are certainly important natural drug resources for medical applications. In scorpions, family Buthidae has always been interesting from the public health perspective in terms of their dangerous venoms. Many studies have concentrated on non-Buthidae families and reported several new venom peptides and proteins which have shown unique primary structures and biological activities [52–55]. However, the first disulfide-bridged peptide toxin extracted from a non-buthid scorpion was St20 from Scorpiops tibetanus. This peptide has immunosuppressive and anti-inflammatory effects that suggest its potential use as a new peptide medicine for human diseases [56]. Scorpion toxins have been used in variety of fields, including biotechnology (examining the effects on ion channels), identifying cancer mass [57], treating cancer [58], and to treat neuronal [59], autoimmune [60], and cardiovascular diseases [61]. The venoms of Pandinus imperator and Scorpio maurus palmatus have peptides named imperatoxin A (IpTxa) and maurocalcin (MCa),